Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

基于我们的小鼠数据，我们制定了一项1期和2期方案，采用阿仑单抗、400cGy全身照射（TBI）和移植后环磷酰胺（PT-Cy）剂量递增，队列1为0mg/kg，队列2为50mg/kg，队列3为100mg/kg。共有21例镰状细胞病患者和2例地中海贫血患者接受了移植，并出现了肝硬化、肺动脉高压、心力衰竭和终末期肾病等并发症。移植率从第一队列的1/3（33%）提高到第二队列的5/8(63%)，第三队列的10/12（83%）。在随后的队列中，供体骨髓和CD3嵌合的百分比也有所改善。总生存率为86.9%；移植后100天前无死亡病例。目前，第一队列中有0%，第二队列中有25%，第三队列中有50%的患者没有患病。没有2-4级急性或慢性广泛移植物抗宿主病（GVHD）。因此，我们已经证明PT-Cy可以改善早期死亡风险高的SCD患者的移植。由于我们已经达到了研究的停止规则，我们最近开始了一项新的方案，增加了额外的免疫抑制，试图提高成功率。我们还将寻找与移植物排斥反应相关的早期生物标志物，试图在早期和可能更可逆的状态下识别移植物排斥反应，并探索移植物移植和耐受性诱导的机制。

Based on our murine data, we developed a phase 1 and 2 protocol employing alemtuzumab, 400cGy total body irradiation (TBI) and escalating doses of post-transplant cyclophosphamide (PT-Cy) ranging from 0mg/kg in cohort 1 and 50mg/kg in cohort 2 to 100mg/kg in cohort 3. A total of 21 patients with sickle cell disease and 2 patients with beta thalassemia were transplanted and had complications including cirrhosis, pulmonary hypertension, heart failure, and end-stage renal disease. The engraftment rate improved from 1/3 (33%) in the first cohort, to 5/8 (63%) in the second cohort to 10/12 (83%) in the third cohort. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. Overall survival is 86.9%; there was no mortality before 100 days post-transplant. At present, 0% in the first cohort, 25% in the second cohort, and 50% in the third cohort remain free of their disease. There was no Grade 2-4 acute or chronic extensive graft-versus-host disease (GVHD). Therefore, we have shown that PT-Cy improves engraftment in patients with SCD who are at high risk for early mortality. As we have reached stopping rules for the study, we recently opened a new protocol which has added additional immunosuppression in an attempt to improve the success rate. We will also search for early biomarkers associated with graft rejection in an attempt to identify graft rejection at an early and potentially more reversible state and explore mechanisms of engraftment and tolerance induction.